The splicing factor DHX38 enables retinal development through safeguarding genome integrity

Kui Sun; Yunqiao Han; Jingzhen  Li; Shanshan  Yu; Yuwen Huang; Yangjun Zhang; James Reilly; Jiayi Tu; Pan Gao; Danna Jia; Xiang Chen; Hualei Hu; Mengmeng Ren; Pei Li; Jiong Luo; Xiang Ren; Xianqin  Zhang; Xinhua Shu; Fei Liu; Mugen Liu; Zhaohui Tang

doi:10.1016/j.isci.2023.108103

The splicing factor DHX38 enables retinal development through safeguarding genome integrity

Kui Sun, Yunqiao Han, Jingzhen Li, Shanshan Yu, Yuwen Huang, Yangjun Zhang, James Reilly, Jiayi Tu, Pan Gao, Danna Jia, Xiang Chen, Hualei Hu, Mengmeng Ren, Pei Li, Jiong Luo, Xiang Ren, Xianqin Zhang, Xinhua Shu, Fei Liu^*, Mugen Liu^*Zhaohui Tang^*

^*Corresponding author for this work

Biological and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

54 Downloads (Pure)

Abstract

DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, we
demonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control.

Original language	English
Article number	108103
Journal	iScience
Volume	26
Issue number	11
Early online date	30 Sept 2023
DOIs	https://doi.org/10.1016/j.isci.2023.108103
Publication status	Published - 17 Nov 2023

Keywords

Developmental genetics
Molecular physiology

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Documents and Links

10.1016/j.isci.2023.108103

Final published version.Final published version, 5.52 MBLicence: CC BY-NC-ND

Cite this

@article{4652369105734d06a1a83aee183a9a4a,

title = "The splicing factor DHX38 enables retinal development through safeguarding genome integrity",

abstract = "DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, wedemonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control.",

keywords = "Developmental genetics, Molecular physiology",

author = "Kui Sun and Yunqiao Han and Jingzhen Li and Shanshan Yu and Yuwen Huang and Yangjun Zhang and James Reilly and Jiayi Tu and Pan Gao and Danna Jia and Xiang Chen and Hualei Hu and Mengmeng Ren and Pei Li and Jiong Luo and Xiang Ren and Xianqin Zhang and Xinhua Shu and Fei Liu and Mugen Liu and Zhaohui Tang",

year = "2023",

month = nov,

day = "17",

doi = "10.1016/j.isci.2023.108103",

language = "English",

volume = "26",

journal = "iScience",

publisher = "Cell Press",

number = "11",

}

TY - JOUR

T1 - The splicing factor DHX38 enables retinal development through safeguarding genome integrity

AU - Sun, Kui

AU - Han, Yunqiao

AU - Li, Jingzhen

AU - Yu, Shanshan

AU - Huang, Yuwen

AU - Zhang, Yangjun

AU - Reilly, James

AU - Tu, Jiayi

AU - Gao, Pan

AU - Jia, Danna

AU - Chen, Xiang

AU - Hu, Hualei

AU - Ren, Mengmeng

AU - Li, Pei

AU - Luo, Jiong

AU - Ren, Xiang

AU - Zhang, Xianqin

AU - Shu, Xinhua

AU - Liu, Fei

AU - Liu, Mugen

AU - Tang, Zhaohui

PY - 2023/11/17

Y1 - 2023/11/17

N2 - DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, wedemonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control.

AB - DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, wedemonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control.

KW - Developmental genetics

KW - Molecular physiology

U2 - 10.1016/j.isci.2023.108103

DO - 10.1016/j.isci.2023.108103

M3 - Article

VL - 26

JO - iScience

JF - iScience

IS - 11

M1 - 108103

ER -

The splicing factor DHX38 enables retinal development through safeguarding genome integrity

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Documents and Links

Fingerprint

Cite this